There is little doubt that we are in the midst of a worldwide epidemic of diabetes. Insulin resistance, defined by the inability to respond to normal circulating levels of insulin, is recognized as a characteristic trait of the disease, most often occurring in obese patients. Emerging data suggests an inflammatory link between obesity and diabetes. However, understanding the specific lesions that cause insulin resistance in patients with Type 2 diabetes will first require a better grasp of the cell biology of insulin action, and the interplay between the innate immune system and insulin action. To this end, the molecular events involved in the regulation of glucose uptake by insulin will be investigated, with special attention to the underlying basis for the specificity of actions of the hormone. Aim 1 will evaluate molecular mechanisms responsible for improved insulin sensitivity in the face of a high fat diet in mice with a targeted deletion in the CAP gene. We will evaluate the migration and activation of adipose tissue macrophages in these mice, and perform in vitro studies to elucidate the molecular defects in these cells resulting from CAP knockout. In Aim 2 the action of CAP in adipocytes will be studied, with particular attention to its role in supporting Cbl phosphorylation and downstream signaling, and in assembling actin-based complexes at the plasma membrane. Aim 3 will focus on the CAP family member Vinexin, and its genetic interactions with CAP. We will study mice with a targeted deletion in the Vinexin gene, and cross these with CAPKO mice, to elucidate the role of this family of proteins in the regulation of glucose homeostasis. Together, these approaches will allow for the evaluation of the importance of this novel pathway in insulin action, setting the stage for future investigations into its potential role in the development of diabetes. PUBLIC HEALTH RELEVANCE There is little doubt that we are in the midst of a worldwide epidemic of diabetes. Insulin resistance, defined by the inability to respond to normal circulating levels of insulin, is recognized as a characteristic trait of the disease, most often occurring in obese patients. Emerging data suggests an inflammatory link between obesity and diabetes. We will strive to understand the specific lesions that cause insulin resistance in patients with Type 2 diabetes by first gaining a better grasp of the cell biology of insulin action, and the interplay between the innate immune system and insulin action.